美国脂质协会他汀药物肝脏安全性评估简介

最近．美国国家脂质协会（National Lipid Association, NLA）邀请致力于非酒精性脂肪性肝病（nonalcoholic fatty liver disease, NAFLD）,脂质代谢紊乱和药物性肝损害研究方面的肝脏病学专家加盟他汀安全性工作组．旨在对他汀肝脏安全性问题进行一次全面的、严格的、学术的、最新的以及无偏见的评估。本文主要介绍NLA与肝病专家委员之间的对话。     

Monoclonal antibodies recognizing epitopes on the extracellular face and intracellular N-terminus of the human erythrocyte anion transporter (band 3) and their application to the analysis of South East Asian ovalocytes

This report describes the production and characterization of 13 rodent monoclonal antibodies to the human erythrocyte anion transport protein AE1 (syn. band 3). Eleven antibodies (4 murine and 7 rat) recognize epitopes dependent on the integrity of the third extracellular loop of the protein. Two antibodies (1 murine and 1 rat) recognize epitopes on the N-terminal cytoplasmic domain. Quantitative binding studies using radioiodinated IgG and Fab fragments of antibodies to extracellular epitopes on AE1 ranged from 77,000 to 313,000 (IgG) and from 241,000 to 772,000 (Fab) molecules bound at saturation. The results indicate that the epitopes recognized by different antibodies vary in their accessibility and suggest that there is heterogeneity in the organization of individual AE1 molecules in the red blood cell membrane. Quantitative binding studies on South East Asian ovalocytes using several antibodies to AE1 and an anti-Wrb show a marked reduction in the number of antibody molecules bound at saturation. These results are consistent with the existence of highly cooperative interactions between transmembrane domains of AE1 in normal erythrocytes and the disruption of these interactions in the variant AE1 found in South East Asian ovalocytes.     

Parentage analysis by endonuclease shattering of hypervariable DNA

Single-locus DNA probes for tandem repeat sequences are now used in conjunction with particular endonucleases to characterize heritable restriction fragment lengths in parentage tests. Southern blots of this type, however, demonstrate only two attributes of an allele: its length and the presence of nucleotide sequences that are complementary to the probe. Not all restriction fragments of the same apparent length that react with the same probe are identical. Differences between comigrating fragments can be detected by the selection of a restriction enzyme that recognizes sites in a subset of the repeat sequences, and the information content of these loci is therefore increased. This report describes a paternity case in which two brothers appeared, after DNA phenotyping using Hinf I, to be the father. A second phenotyping using Hae III excluded one of the brothers.     

Trabecular bone architecture in female renal allograft recipients-- assessed by computed tomography

BACKGROUND: Osteopenia with decreased bone mineral density (BMD) is a frequent finding in renal allograft recipients. Data concerning the bone architecture in these patients do not exist, however. METHODS: We compared the bone architecture of 33 randomly assigned women (age 49 +/- 12 years), who had received renal allografts 5.6 +/- 5.3 years before the investigation, with 74 women (age 50 +/- 14 years) who were admitted for osteodensitometry. All patients underwent single-energy computed tomography (SEQCT) and a midvertebral high-resolution tomography with computer-assisted analysis of the trabecular vertebral body architecture. RESULTS: Progressive alteration of bone architecture was associated with increasing vertebral height loss of the vertebral body. Height reduction of a vertebral body of more than 15% was associated with a significantly lower BMD (-2.3 +/- 0.8 versus -1.1 +/- 1.1 standard deviations below normal BMD), a lower trabecular bone area (13 +/- 8% versus 42 +/- 22%) and a lower trabecular diameter (1.4 +/- 0.5 mm versus 2.2 +/- 0.8 mm) compared to recipients without height reduction. In comparison to a matched group of patients with similarly reduced BMD (1.1 +/- 1.2 versus 1.2 +/- 1.1 SD below normal BMD), renal allograft recipients showed a lower number of trabecular plates (5.6 +/- 3.1 versus 7.0 +/- 3.7) and a smaller intertrabecular surface (54 +/- 116 mm versus 75 +/- 138 mm). CONCLUSIONS: Alterations of bone architecture in renal allograft recipients were associated with progressive vertebral height loss. Despite similar bone mineral density, differences of bone architecture could be observed between renal allograft recipients and patients with osteoporosis.      

Associations of parent and staff factors with parent engagement in after‐school programs

This 2‐study research examined staff and parent predictors of parent engagement in after‐school programs. A parent engagement measure tailored to after‐school programs was developed based on existing theory and literature. Two distinct factors, parent engagement and parent participation, emerged from factor analyses and were subsequently tested. A 2‐level model was run on 4 program/staff and 6 parent predictors using staff and parent data from 26 after‐school program sites (Study 1) and nine sites (Study 2). Program quality, staff educational levels, and length of employment in the after‐school program were significantly associated with parent engagement and parent participation but in opposite directions, with other findings contrary to hypotheses. For parent factors of engagement and participation, there was a significant positive association between parental age and parent engagement, while having more than 2 children in a program was significantly and positively associated with parent participation only. Results and implications are discussed.     

Evaluation of multiple transfer of DNA using mock case scenarios

DNA transfer and its possible role in explaining the presence of a biological sample at a crime scene is becoming more prevalent in criminal investigations and related court proceedings. To assist understanding of DNA transfer and assess the extent to which we can utilise already available information regarding transfer of DNA we compare transfer rates determined from mock multi-step transfer scenarios with transfer rates predicted by the application of currently available transfer rate data. The transfer results obtained from the scenarios tested were, in some instances, different (both lower and higher rates) from those predicted. These discrepancies are most likely the result of the impact of as yet untested variables. These may include the variations in substrate type, transfer area size and environmental factors such as temperature and humidity among others. Whilst detailed re-enactments of proposed transfer scenarios, that take into account the many possibly relevant aspects affecting transfer are desirable, to provide an accurate likelihood estimate, these are not always possible. The application of detailed transfer rate tables that include data on the many factors affecting transfer could provide a useful substitute for evaluating the likelihood of specific transfer events. The value and accuracy derived from applying such tables will improve as more research in this area is conducted and the tables expanded and refined.     

Therapeutic Potentials of Ecto‐Nucleoside Triphosphate Diphosphohydrolase,Ecto‐Nucleotide Pyrophosphatase/Phosphodiesterase,Ecto‐5′‐Nucleotidase,and Alkaline Phosphatase Inhibitors

The modulatory role of extracellular nucleotides and adenosine in relevance to purinergic cell signaling mechanisms has long been known and is an object of much research worldwide. These extracellular nucleotides are released by a variety of cell types either innately or as a response to patho‐physiological stress or injury. A variety of surface‐located ecto‐nucleotidases (of four major types; nucleoside triphosphate diphosphohydrolases or NTPDases, nucleotide pyrophosphatase/phosphodiesterases or NPPs, alkaline phosphatases APs or ALPs, and ecto‐5′‐nucleotidase or e5NT) are responsible for meticulously controlling the availability of these important signaling molecules (at their respective receptors) in extracellular environment and are therefore crucial for maintaining the integrity of normal cell functioning. Overexpression of many of these ubiquitous ecto‐enzymes has been implicated in a variety of disorders including cell adhesion, activation, proliferation, apoptosis, and degenerative neurological and immunological responses. Selective inhibition of these ecto‐enzymes is an area that is currently being explored with great interest and hopes remain high that development of selective ecto‐nucleotidase inhibitors will prove to have many beneficial therapeutic implications. The aim of this review is to emphasize and focus on recent developments made in the field of inhibitors of ecto‐nucleotidases and to highlight their structure activity relationships wherever possible. Most recent and significant advances in field of NTPDase, NPP, AP, and e5NT inhibitors is being discussed in detail in anticipation of providing prolific leads and relevant background for research groups interested in synthesis of selective ecto‐nucleotidase inhibitors.